Methods for predicting drug responsiveness in cancer patients

Abstract

The present invention features methods, devices, and kits for detecting gene expression in a patient with a cancer or determining responsive of a patient with a cancer to a treatment, such as treatment with 2X-121 or a pharmaceutically acceptable salt thereof. The invention further includes methods of treating a patient with a cancer by administering a treatment, e.g., treatment with 2X-121 or a pharmaceutically acceptable salt thereof, in particular when the patient is determined to be responsive to the treatment based on the expression of the biomarkers described herein.

1 . A method of determining responsiveness of a subject with a cancer to 2X-121 or a pharmaceutically acceptable salt thereof comprising:
 (a) contacting a sample from the subject comprising one or more nucleic acid molecules with a device comprising:
 (i) one or more single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of one or more biomarkers of sensitivity selected from the biomarkers of Table 2; and/or 
 (ii) one or more single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of one or more biomarkers of resistance selected from the biomarkers of Table 3; and 
   (b) measuring hybridization between the one or more nucleic acid molecules from the sample and the single-stranded nucleic acid molecules of the device to detect a level of expression of the one or more biomarkers of sensitivity and/or the one or more biomarkers of resistance.   
     
     
         2 . The method of  claim 1 , wherein the subject is determined to be responsive to 2X-121 or the pharmaceutically acceptable salt thereof if:
 (i) the level of expression of the one or more biomarkers of sensitivity is substantially similar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be sensitive to 2X-121 or the pharmaceutically acceptable salt thereof;   (ii) the level of expression of the one or more biomarkers of resistance is substantially similar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be sensitive to 2X-121 or the pharmaceutically acceptable salt thereof;   (iii) the level of expression of the one or more biomarkers of sensitivity is substantially dissimilar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be resistant to 2X-121 or the pharmaceutically acceptable salt thereof; and/or   (iv) the level of expression of the one or more biomarkers of resistance is substantially dissimilar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be resistant to 2X-121 or the pharmaceutically acceptable salt thereof.   
     
     
         3 . The method of  claim 1  or  2 , further comprising selecting the subject determined to be responsive to treatment with 2X-121 or the pharmaceutically acceptable salt thereof for administration of 2X-121 or the pharmaceutically acceptable salt thereof. 
     
     
         4 . The method of  claim 1 , further comprising administering one or more cancer therapies other than 2X-121 or the pharmaceutically acceptable salt thereof to the subject determined to be resistant to 2X-121 or the pharmaceutically acceptable salt thereof. 
     
     
         5 . The method of  claim 4 , wherein:
 (i) the level of expression of the one or more biomarkers of sensitivity is substantially dissimilar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be sensitive to 2X-121 or a pharmaceutically acceptable salt thereof;   (ii) the level of expression of the one or more biomarkers of resistance is substantially dissimilar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be sensitive to 2X-121 or a pharmaceutically acceptable salt thereof;   (iii) the level of expression of the one or more biomarkers of sensitivity is substantially similar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be resistant to 2X-121 or a pharmaceutically acceptable salt thereof; and/or   (iv) the level of expression of the one or more biomarkers of resistance is substantially similar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be resistant to 2X-121 or a pharmaceutically acceptable salt thereof.   
     
     
         6 . The method of any one of  claims 2 - 5 , wherein:
 (i) sensitivity of the cell or tissue known to be sensitive to 2X-121 or the pharmaceutically acceptable salt thereof is based on GI50 data of NCI60 cell lines; and/or   (ii) resistance of the cell or tissue known to be resistant to 2X-121 or the pharmaceutically acceptable salt thereof is based on GI50 data of NCI60 cell lines.   
     
     
         7 . The method of  claim 4 , wherein the one or more cancer therapies comprises surgery, radiation, or a therapeutic agent. 
     
     
         8 . The method of  claim 7 , wherein the therapeutic agent is selected from the group consisting of a histone deacetylase (HDAC) inhibitor, a PD1/PD-L1 inhibitor, ipilimumab, bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, prednisone, dexamethasone, cyclophosphamide, vincristine, doxorubicin, melphalan, capecitabine, tegafur, irinotecan, oxaliplatin, cetuximab, leucovorin, SN-38, everolimus, temsirolimus, bleomycin, lomustine, depsipeptide, carboplatin, erlotinib, gemcitabine, mitoxantrone, cisplatin, busulfan, epirubicin, arsenic trioxide, bendamustine, fulvestrant, teniposide, adriamycin, decitabine, estramustine, etoposide, azaguanine, aclarubicin, mitoxantrone, mitomycin, paclitaxel, taxotere, Irofulven, 5-FU, ara-c, methylprednisolone, methotrexate, methyl-gag, belinostat, carboplatin, idarubicin, IL4-PR38, valproic acid, all-trans retinoic acid (ATRA), cytoxan, topotecan, suberoylanilide hydroxamic acid, leukeran, fludarabine, vinblastine, dacarbazine, hydroxyurea, tegafur, daunorubicin, mechlorethamine, streptozocin, carmustine, mercaptopurine, dactinomycin, tretinoin, ifosfamide, tamoxifen, floxuridine, thioguanine, PSC 833, herceptin, bevacizumab, celecoxib, iressa, anastrozole, letrozole, and rituximab. 
     
     
         9 . A method of treating a cancer in a subject in need thereof comprising administering 2X-121 or a pharmaceutically acceptable salt thereof to the subject, wherein the subject has been determined to be responsive to 2X-121 or the pharmaceutically acceptable salt thereof according to the method of  claim 1 . 
     
     
         10 . A method of treating a subject with a cancer, the method comprising:
 (a) contacting a sample from the subject comprising one or more nucleic acid molecules with a device comprising:
 (i) one or more single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of one or more biomarkers of sensitivity selected from the biomarkers of Table 2; and/or 
 (ii) one or more single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of one or more biomarkers of resistance selected from the biomarkers of Table 3; 
   (b) measuring hybridization between the one or more nucleic acid molecules from the sample and the single-stranded nucleic acid molecules of the device to detect a level of expression of the one or more biomarkers of sensitivity and/or the one or more biomarkers of resistance; and   (c) administering 2X-121 or a pharmaceutically acceptable salt thereof to the subject.   
     
     
         11 . The method of  claim 10 , wherein the subject is administered 2X-121 or the pharmaceutically acceptable salt thereof if:
 (i) the level of expression of the one or more biomarkers of sensitivity is substantially similar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be sensitive to 2X-121 or the pharmaceutically acceptable salt thereof;   (ii) the level of expression of the one or more biomarkers of resistance is substantially similar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be sensitive to 2X-121 or the pharmaceutically acceptable salt thereof;   (iii) the level of expression of the one or more biomarkers of sensitivity is substantially dissimilar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be resistant to 2X-121 or the pharmaceutically acceptable salt thereof; and/or   (iv) the level of expression of the one or more biomarkers of resistance is substantially dissimilar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be resistant to 2X-121 or the pharmaceutically acceptable salt thereof.   
     
     
         12 . The method of  claim 11 , wherein:
 (i) sensitivity of the cell or tissue known to be sensitive to 2X-121 or the pharmaceutically acceptable salt thereof is based on GI50 data of NCI60 cell lines; and/or   (ii) resistance of the cell or tissue known to be resistant to 2X-121 or the pharmaceutically acceptable salt thereof is based on GI50 data of NCI60 cell lines.   
     
     
         13 . The method of  claim 10 , further comprising administering one or more additional therapies to the subject prior to, concurrently, or after administration of 2X-121 or the pharmaceutically acceptable salt thereof. 
     
     
         14 . The method of  claim 13 , wherein the one or more additional therapies comprises surgery, radiation, or a therapeutic agent. 
     
     
         15 . The method of  claim 14 , wherein the therapeutic agent is selected from the group consisting of a histone deacetylase (HDAC) inhibitor, a PD1/PD-L1 inhibitor, ipilimumab, bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, prednisone, dexamethasone, cyclophosphamide, vincristine, doxorubicin, melphalan, capecitabine, tegafur, irinotecan, oxaliplatin, cetuximab, leucovorin, SN-38, everolimus, temsirolimus, bleomycin, lomustine, depsipeptide, carboplatin, erlotinib, gemcitabine, mitoxantrone, cisplatin, busulfan, epirubicin, arsenic trioxide, bendamustine, fulvestrant, teniposide, adriamycin, decitabine, estramustine, etoposide, azaguanine, aclarubicin, mitoxantrone, mitomycin, paclitaxel, taxotere, Irofulven, 5-FU, ara-c, methylprednisolone, methotrexate, methyl-gag, belinostat, carboplatin, idarubicin, IL4-PR38, valproic acid, all-trans retinoic acid (ATRA), cytoxan, topotecan, suberoylanilide hydroxamic acid, leukeran, fludarabine, vinblastine, dacarbazine, hydroxyurea, tegafur, daunorubicin, mechlorethamine, streptozocin, carmustine, mercaptopurine, dactinomycin, tretinoin, ifosfamide, tamoxifen, floxuridine, thioguanine, PSC 833, herceptin, bevacizumab, celecoxib, iressa, anastrozole, letrozole, and rituximab. 
     
     
         16 . The method of  claim 15 , wherein the therapeutic agent is administered parenterally, enterally, or topically. 
     
     
         17 . The method of  claim 16 , wherein the therapeutic agent is administered intravenously, intramuscularly, transdermally, intradermally, intra-arterially, intracranially, subcutaneously, intraorbitally, intraventricularly, intraspinally, intraperitoneally, or intranasally. 
     
     
         18 . The method of any one of  claims 3  and  9 - 17 , wherein 2X-121 or the pharmaceutically acceptable salt thereof is administered parenterally, enterally, or topically. 
     
     
         19 . The method of  claim 18 , wherein 2X-121 or the pharmaceutically acceptable salt thereof is administered intravenously, intramuscularly, transdermally, intradermally, intra-arterially, intracranially, subcutaneously, intraorbitally, intraventricularly, intraspinally, intraperitoneally, or intranasally. 
     
     
         20 . The method of  claim 18 , wherein 2X-121 or the pharmaceutically acceptable salt thereof is administered orally. 
     
     
         21 . The method of any one of  claims 3  and  9 - 20 , comprising administering 2X-121 or the pharmaceutically acceptable salt thereof to the subject two or more times. 
     
     
         22 . The method of  claim 21 , comprising administering 2X-121 or the pharmaceutically acceptable salt thereof to the subject one or more times daily, weekly, every two weeks, every three weeks, or monthly. 
     
     
         23 . The method of  claim 22 , comprising administering 2X-121 or the pharmaceutically acceptable salt thereof to the subject once daily. 
     
     
         24 . The method of any one of  claims 3  and  9 - 23 , comprising administering a second dose of 2X-121 or the pharmaceutically acceptable salt thereof to the subject two weeks, three weeks, four weeks, or five weeks after administration of a first dose of 2X-121 or the pharmaceutically acceptable salt thereof. 
     
     
         25 . The method of any one of  claims 3  and  9 - 24 , wherein 2X-121 or the pharmaceutically acceptable salt thereof is administered in a dosage form. 
     
     
         26 . The method of  claim 25 , wherein 2X-121 or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 5-5000 mg. 
     
     
         27 . The method of  claim 26 , wherein 2X-121 or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 10 mg, 50 mg, or 200 mg. 
     
     
         28 . The method of  claim 26 , wherein 2X-121 or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 50-800 mg. 
     
     
         29 . The method of  claim 28 , wherein 2X-121 or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 600 mg. 
     
     
         30 . The method of any one of  claims 3  and  9 - 29 , wherein the contacting step (a) and the measuring step (b) occur prior to, concurrent to, or after administration of 2X-121 or the pharmaceutically acceptable salt thereof to the subject. 
     
     
         31 . The method of any one of  claims 3  and  9 - 30 , wherein the contacting step (a) and/or the measuring step (b) occur multiple times. 
     
     
         32 . The method of any one of  claims 1 - 31 , wherein the device is a microarray. 
     
     
         33 . The method of  claim 32 , wherein the microarray is a deoxyribonucleic acid (DNA)-based platform. 
     
     
         34 . The method of any one of  claims 1 - 33 , wherein the device comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more single-stranded nucleic acid molecules of (i) and/or (ii). 
     
     
         35 . The method of any one of  claims 1 - 34 , wherein the one or more single-stranded nucleic acid molecules of the device have a length in the range of 10-100 nucleotides. 
     
     
         36 . The method of  claim 35 , wherein the one or more single-stranded nucleic acid molecules have a length in the range of 20-60 nucleotides. 
     
     
         37 . The method of any one of  claims 1 - 36 , wherein the method comprises converting the level of expression of the one or more biomarkers of sensitivity and/or the one or more biomarkers of resistance into a mean score, wherein the mean score indicates the responsiveness of the subject to 2X-121 or the pharmaceutically acceptable salt thereof. 
     
     
         38 . The method of  claim 37 , further comprising subtracting the mean score for the one or more biomarkers of resistance from the mean score for the one or more biomarkers of sensitivity to obtain a difference score, wherein the difference score indicates the responsiveness of the subject to 2X-121 or the pharmaceutically acceptable salt thereof. 
     
     
         39 . The method of  claim 37  or  38 , wherein the mean score and/or the difference score above a cutoff value indicates that the subject is responsive to 2X-121 or the pharmaceutically acceptable salt thereof. 
     
     
         40 . The method of  claim 39 , wherein the cutoff value is about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or greater. 
     
     
         41 . The method of any one of  claims 1 - 40 , wherein the level of expression of the one or more biomarkers of sensitivity and/or the one or more biomarkers of resistance is determined by microarray analysis or nucleic acid amplification methods. 
     
     
         42 . The method of  claim 41 , wherein the nucleic acid amplification method is reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). 
     
     
         43 . The method of any one of  claims 1 - 42 , wherein:
 (i) the level of expression of the biomarkers of sensitivity is determined by detecting the level of mRNA transcribed from a gene coding one or more of the biomarkers of Table 2; and/or   (ii) the level of expression of the biomarkers of resistance is determined by detecting the level of mRNA transcribed from a gene coding one or more of the biomarkers of Table 3.   
     
     
         44 . The method of any one of  claims 1 - 43 , wherein the biomarkers of sensitivity are selected from:
 (a) one or more of SEQ ID NOs: 1-25;   (b) one or more of SEQ ID NOs: 26-50;   (c) one or more of SEQ ID NOs: 51-75;   (d) one or more of SEQ ID NOs: 76-100;   (e) one or more of SEQ ID NOs: 101-125;   (f) one or more of SEQ ID NOs: 126-150;   (g) one or more of SEQ ID NOs: 151-172; and/or   (h) one or more of SEQ ID NOs: 1-172.   
     
     
         45 . The method of any one of  claims 1 - 44 , wherein the biomarkers of resistance are selected from:
 (a) one or more of SEQ ID NOs: 173-200;   (b) one or more of SEQ ID NOs: 201-225;   (c) one or more of SEQ ID NOs: 226-250;   (d) one or more of SEQ ID NOs: 251-275;   (e) one or more of SEQ ID NOs: 276-300;   (f) one or more of SEQ ID NOs: 301-325;   (g) one or more of SEQ ID NOs: 326-350;   (h) one or more of SEQ ID NOs: 351-375;   (i) one or more of SEQ ID NOs: 376-400;   (j) one or more of SEQ ID NOs: 401-414; and/or   (k) one or more of SEQ ID NOs: 173-414.   
     
     
         46 . The method of any one of  claims 1 - 45 , wherein:
 (i) the biomarkers of sensitivity are selected from at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 105, at least 110, at least 115, at least 120, at least 125, at least 130, at least 135, at least 140, at least 145, at least 150, at least 155, at least 160, at least 165, at least 170, or at least 172 of the biomarkers of Table 2; and/or   (ii) the biomarkers of resistance are selected from at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 105, at least 110, at least 115, at least 120, at least 125, at least 130, at least 135, at least 140, at least 145, at least 150, at least 155, at least 160, at least 165, at least 170, at least 175, at least 180, at least 185, at least 190, at least 195, at least 200, at least 205, at least 210, at least 215, at least 220, at least 225, at least 230, at least 235, at least 240, or at least 242 of the biomarkers of Table 3.   
     
     
         47 . The method of any one of  claims 1 - 45 , wherein:
 (i) the biomarker of sensitivity is SRSF7 (SEQ ID NO: 1); and/or   (ii) the biomarker of resistance is HLA-E (SEQ ID NO: 173 or 174 or 178).   
     
     
         48 . The method of any one of  claims 1 - 47 , wherein the cancer is selected from a solid tumor cancer and a hematological cancer. 
     
     
         49 . The method of any one of  claims 1 - 48 , wherein the cancer is selected from the group consisting of multiple myeloma, breast cancer, acute myelogenous leukemia (AML), acute lympho-blastic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), chronic myelogenous leukemia-chronic phase (CMLCP), diffuse large B-cell lymphoma (DLBCL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), Hodgkin's lymphoma, hepatocellular carcinoma (HCC), cervical cancer, prostate cancer, kidney cancer, renal cell carcinoma (RCC), esophageal cancer, melanoma, glioma, pancreatic cancer, ovarian cancer, gastrointestinal stromal tumors (GIST), sarcoma, estrogen receptor-positive (ERpos) breast cancer, lung cancer, non-small cell lung carcinoma (NSCLC), mesothelioma, intestinal cancer, colon cancer, bladder cancer, adrenal cancer, gallbladder cancer, and squamous cell carcinoma of the head and neck (SCCHN). 
     
     
         50 . The method of  claim 49 , wherein the cancer is breast cancer. 
     
     
         51 . The method of  claim 50 , wherein the breast cancer is estrogen receptor-positive (ER pos) breast cancer or is a metastatic form of breast cancer. 
     
     
         52 . The method of  claim 49 , wherein the cancer is ovarian cancer. 
     
     
         53 . The method of  claim 49 , wherein the cancer is pancreatic cancer. 
     
     
         54 . The method of any one of  claims 1 - 53 , wherein the subject has recurrence of cancer. 
     
     
         55 . The method of any one of  claims 1 - 54 , wherein the sample from the subject is a tumor sample. 
     
     
         56 . A composition comprising 2X-121 or a pharmaceutically acceptable salt thereof for use in treating a cancer in a subject, wherein the subject has been determined to be responsive to 2X-121 or the pharmaceutically acceptable salt thereof according to the method of  claim 1  or  2 . 
     
     
         57 . A composition comprising 2X-121 or a pharmaceutically acceptable salt thereof for use in treating a cancer in a subject, wherein the subject has been determined to be responsive to 2X-121 or the pharmaceutically acceptable salt thereof by:
 (a) contacting a sample from the subject comprising one or more nucleic acid molecules with a device comprising:
 (i) one or more single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of one or more biomarkers of sensitivity selected from the biomarkers of Table 2; and/or 
 (ii) one or more single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of one or more biomarkers of resistance selected from the biomarkers of Table 3; 
   (b) measuring hybridization between the one or more nucleic acid molecules from the sample and the single-stranded nucleic acid molecules of the device to detect a level of expression of the one or more biomarkers of sensitivity and/or the one or more biomarkers of resistance; and   (c) determining the subject to be responsive to 2X-121 or the pharmaceutically acceptable salt thereof if:
 (i) the level of expression of the one or more biomarkers of sensitivity is substantially similar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be sensitive to 2X-121 or the pharmaceutically acceptable salt thereof; 
 (ii) the level of expression of the one or more biomarkers of resistance is substantially similar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be sensitive to 2X-121 or the pharmaceutically acceptable salt thereof; 
 (iii) the level of expression of the one or more biomarkers of sensitivity is substantially dissimilar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be resistant to 2X-121 or the pharmaceutically acceptable salt thereof; and/or 
 (iv) the level of expression of the one or more biomarkers of resistance is substantially dissimilar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be resistant to 2X-121 or the pharmaceutically acceptable salt thereof. 
   
     
     
         58 . The composition for use according to  claim 57 , wherein:
 (i) sensitivity of the cell or tissue known to be sensitive to 2X-121 or the pharmaceutically acceptable salt thereof is based on GI50 data of NCI60 cell lines; and/or   (ii) resistance of the cell or tissue known to be resistant to 2X-121 or the pharmaceutically acceptable salt thereof is based on GI50 data of NCI60 cell lines.   
     
     
         59 . The composition for use according to  claim 57  or  58 , wherein the contacting step (a) and/or the measuring step (b) occur multiple times. 
     
     
         60 . The composition for use according to any one of  claims 57 - 59 , wherein the device is a microarray, wherein optionally the microarray is a deoxyribonucleic acid (DNA)-based platform. 
     
     
         61 . The composition for use according to any one of  claims 57 - 60 , wherein the device comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more single-stranded nucleic acid molecules of (i) and/or (ii). 
     
     
         62 . The composition for use according to any one of  claims 57 - 61 , wherein the one or more single-stranded nucleic acid molecules of the device have a length in the range of 10-100 nucleotides, wherein optionally the one or more single-stranded nucleic acid molecules have a length in the range of 20-60 nucleotides. 
     
     
         63 . The composition for use according to any one of  claims 57 - 62 , wherein step (c) comprises converting the level of expression of the one or more biomarkers of sensitivity and/or the one or more biomarkers of resistance into a mean score, wherein the mean score indicates the responsiveness of the subject to 2X-121 or the pharmaceutically acceptable salt thereof. 
     
     
         64 . The composition for use according to  claim 63 , wherein step (c) further comprises subtracting the mean score for the one or more biomarkers of resistance from the mean score for the one or more biomarkers of sensitivity to obtain a difference score, wherein the difference score indicates the responsiveness of the subject to 2X-121 or the pharmaceutically acceptable salt thereof. 
     
     
         65 . The composition for use according to  claim 63  or  64 , wherein the mean score and/or the difference score above a cutoff value indicates that the subject is responsive to 2X-121 or the pharmaceutically acceptable salt thereof, wherein optionally the cutoff value is about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or greater. 
     
     
         66 . The composition for use according to any one of  claims 57 - 65 , wherein the level of expression of the one or more biomarkers of sensitivity and/or the one or more biomarkers of resistance is determined by microarray analysis or nucleic acid amplification methods, wherein optionally the nucleic acid amplification method is reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). 
     
     
         67 . The composition for use according to any one of  claims 57 - 66 , wherein:
 (i) the level of expression of the biomarkers of sensitivity is determined by detecting the level of mRNA transcribed from a gene coding one or more of the biomarkers of Table 2; and/or   (ii) the level of expression of the biomarkers of resistance is determined by detecting the level of mRNA transcribed from a gene coding one or more of the biomarkers of Table 3.   
     
     
         68 . The composition for use according to any one of  claims 57 - 67 , wherein the biomarkers of sensitivity are selected from:
 (a) one or more of SEQ ID NOs: 1-25;   (b) one or more of SEQ ID NOs: 26-50;   (c) one or more of SEQ ID NOs: 51-75;   (d) one or more of SEQ ID NOs: 76-100;   (e) one or more of SEQ ID NOs: 101-125;   (f) one or more of SEQ ID NOs: 126-150;   (g) one or more of SEQ ID NOs: 151-172; and/or   (h) one or more of SEQ ID NOs: 1-172.   
     
     
         69 . The composition for use according to any one of  claims 57 - 68 , wherein the biomarkers of resistance are selected from:
 (a) one or more of SEQ ID NOs: 173-200;   (b) one or more of SEQ ID NOs: 201-225;   (c) one or more of SEQ ID NOs: 226-250;   (d) one or more of SEQ ID NOs: 251-275;   (e) one or more of SEQ ID NOs: 276-300;   (f) one or more of SEQ ID NOs: 301-325;   (g) one or more of SEQ ID NOs: 326-350;   (h) one or more of SEQ ID NOs: 351-375;   (i) one or more of SEQ ID NOs: 376-400;   (j) one or more of SEQ ID NOs: 401-414; and/or   (k) one or more of SEQ ID NOs: 173-414.   
     
     
         70 . The composition for use according to any one of  claims 57 - 69 , wherein:
 (i) the biomarkers of sensitivity are selected from at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 105, at least 110, at least 115, at least 120, at least 125, at least 130, at least 135, at least 140, at least 145, at least 150, at least 155, at least 160, at least 165, at least 170, or at least 172 of the biomarkers of Table 2; and/or   (ii) the biomarkers of resistance are selected from at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 105, at least 110, at least 115, at least 120, at least 125, at least 130, at least 135, at least 140, at least 145, at least 150, at least 155, at least 160, at least 165, at least 170, at least 175, at least 180, at least 185, at least 190, at least 195, at least 200, at least 205, at least 210, at least 215, at least 220, at least 225, at least 230, at least 235, at least 240, or at least 242 of the biomarkers of Table 3.   
     
     
         71 . The composition for use according to any one of  claims 57 - 78 , wherein:
 (i) the biomarker of sensitivity is SRSF7 (SEQ ID NO: 1); and/or   (ii) the biomarker of resistance is HLA-E (SEQ ID NO: 173 or 174 or 178).   
     
     
         72 . The composition for use according to any one of  claims 56 - 71 , wherein the composition is formulated for parenteral, enteral, or topical administration. 
     
     
         73 . The composition for use according to  claim 72 , wherein the composition is formulated for intravenous, intramuscular, transdermal, intradermal, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, or intranasal administration, wherein optionally the composition is formulated for oral administration. 
     
     
         74 . The composition for use according to any one of  claims 56 - 73 , wherein the composition is administered to the subject two or more times. 
     
     
         75 . The composition for use according to  claim 74 , wherein the composition is administered to the subject one or more times daily, weekly, every two weeks, every three weeks, or monthly, wherein optionally the composition is administered to the subject once daily. 
     
     
         76 . The composition for use according to any one of  claims 56 - 75 , wherein the composition is administered to the subject as a second dose, two weeks, three weeks, four weeks, or five weeks after administration of a first dose. 
     
     
         77 . The composition for use according to any one of  claims 56 - 76 , wherein the composition is administered in a dosage form. 
     
     
         78 . The composition for use according to  claim 77 , wherein the composition is administered to the subject at a dose of about 5-5000 mg. 
     
     
         79 . The composition for use according to  claim 78 , wherein the composition is administered to the subject at a dose of about 10 mg, 50 mg, or 200 mg. 
     
     
         80 . The composition for use according to  claim 78 , wherein the composition is administered to the subject at a dose of about 50-800 mg, wherein optionally the composition is administered to the subject at a dose of about 600 mg. 
     
     
         81 . The composition for use according to any one of  claims 56 - 80 , wherein the subject has recurrence of cancer. 
     
     
         82 . The composition for use according to any one of  claims 56 - 81 , wherein the cancer is selected from a solid tumor cancer and a hematological cancer. 
     
     
         83 . The composition according to any one of  claims 56 - 82 , wherein the cancer is selected from the group consisting of multiple myeloma, breast cancer, acute myelogenous leukemia (AML), acute lympho-blastic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), chronic myelogenous leukemia-chronic phase (CMLCP), diffuse large B-cell lymphoma (DLBCL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), Hodgkin's lymphoma, hepatocellular carcinoma (HCC), cervical cancer, prostate cancer, kidney cancer, renal cell carcinoma (RCC), esophageal cancer, melanoma, glioma, pancreatic cancer, ovarian cancer, gastrointestinal stromal tumors (GIST), sarcoma, estrogen receptor-positive (ERpos) breast cancer, lung cancer, non-small cell lung carcinoma (NSCLC), mesothelioma, intestinal cancer, colon cancer, bladder cancer, adrenal cancer, gallbladder cancer, and squamous cell carcinoma of the head and neck (SCCHN). 
     
     
         84 . The composition for use according to  claim 83 , wherein the cancer is breast cancer, wherein optionally the breast cancer is estrogen receptor-positive (ER pos) breast cancer or is a metastatic form of breast cancer. 
     
     
         85 . The composition for use according to  claim 83 , wherein the cancer is ovarian cancer. 
     
     
         86 . The composition for use according to  claim 83 , wherein the cancer is pancreatic cancer. 
     
     
         87 . The composition for use according to any one of  claims 57 - 86 , wherein the sample from the subject is a tumor sample.